Efforts are focused on the design, synthesis and evaluation of polypeptides that are targeted to inhibit, or otherwise modulate key cellular signal transduction processes. The long term goal is to develop effective agents that are selective in inhibiting the oncogenic cell proliferative signal, or to boost the effectiveness of tumor suppressor proteins, and thus could become useful cancer therapeutic agents. Two major projects were undertaken. In one of these the mode of action of the cell cycle inhibitory protein, p21(Waf1/Cip1) was studied. For this purpose the whole protein was synthesized in 20-26 amino acid long overlapping peptides. Two N-terminal non-overlapping regions, separated by an alpha-helical segment, were found to bind to the cyclin/Cdk complex, and to antagonize the kinase inhibitory action of p21. A C- terminal alpha-helical segment was found to suppress P21 - PCNA interactions. In a second project, synthetic methodologies were developed to incorporate a variety of phosphatase resistant tyrosine- phosphate mimicking amino acids into peptides, which were found to be effective inhibitors of growth factor receptor / Src homology region 2 (SH2) domain interactions. Several of these peptides were also highly potent protein tyrosine phosphatase inhibitors. The non-phosphorus containing tyrosine phosphate mimics, O-malonyl-tyrosine (OMT) and its fluorinated analog in peptides, are amenable for derivatization for development of cell permeable prodrugs, and its study is a high priority in this area of endeavor.